The midbrain dopamine (DA) neurons that project to the prefrontal cortex (PFC) are critical for normal cognitive functioning. Consequently, the cognitive dysfunctions observed in schizophrenia have been partially attributed to the diminished amount of DA input to the PFC of patients with this disorder. However, the regulation of DA transmission within the PFC is not only determined by the activity of the DA neurons but also by the levels of the other monoamines, norepinephrine (NE) and serotonin (5-HT), within that area. This is evident in studies showing the importance of NE terminals in removing DA from the extracellular space within the PFC and the importance of DA and 5-HT blockade in the therapeutic efficacy of most atypical antipsychotics. In order to understand better the nature of the interactions between the monoamines within the PFC, dual-labeling immunocytochemistry and electron microscopy will be used to determine 1) whether there are direct structural bases for interactions between DA terminals and terminals containing NE or 5-HT, and 2) whether there are morphological substrates for modulation of DA neurotransmission within the PFC by the transporters for NE and 5-HT. These anatomical studies revealing the relationship of the monoamine innervation of the PFC will contribute to our current knowledge of the organization and function of this complex area, and thereby assist in the development of more efficient therapeutic tools for disorders of PFC function, such as schizophrenia.